4-Desoxy-4-epipodophyllotoxin derivative or pharmaceutically acceptable salt thereof

ABSTRACT

A 4-desoxy-4-epipodophyllotoxin derivative of the following formula ##STR1## wherein R and R 1  are as defined in the specification or a pharmaceutically acceptable salt thereof as well as an antitumor composition comprising such derivative or salt as an active ingredient.

This application is a continuation of application Ser. No. 07/924,079filed as PCT/JP92/0051, Jan. 22, 1992 now abandoned.

TECHNICAL FIELD

The present invention relates to novel 4-desoxy-4-epipodophyllotoxinderivatives and pharmaceutically acceptable salts thereof which haveantitumor activity and are of use as antitumor agents.

BACKGROUND ART

Podophyllotoxin derivatives having antitumor activity have long beenknown and etoposide and teniposide are among them. However, thesecompounds may cause serious adverse reactions including leukopenia,thrombopenia, alopecia, nausea and vomiting so that they cannot beclinically put to use with insured safety. Thus, no satisfactorycompounds has been discovered as yet.

DISCLOSURE OF THE INVENTION

Noting these problems of the prior art, the inventor of the presentinvention explored this field of technology with enthusiasm and foundthat a novel 4-desoxy-4-epipodophyllotoxin derivative of the followinggeneral formula (I) or a pharmaceutically acceptable salt thereof hasvery strong antitumor activity and is useful as an antitumor agent. Thefinding has led to the present invention.

Thus, the present invention provides a 4-desoxy-4-epipodophyllotoxinderivative of the general formula (I): ##STR2## wherein R₁ is a hydrogenatom, a methyl group, a benzyloxycarbonyl group, a lower alkanoyl groupwhich may have one or more halogen atoms or a group of the formula--Si(Rx)(Ry)(Rz) (where Rx, Ry and Rz are the same or different and eachis a lower alkyl group or a phenyl group); R is a lower alkenyl group, alower alkyl group having at least one hydroxyl group, a group of theformula --(CH₂)_(m) CHO (where m is an integer of 0 to 4), a lower alkylgroup having a ketoaldehyde group or a group of the formula --(CH₂)_(n)NR₂ R₃ (where n is an integer of 1 to 6); R₂ and R₃ are the same ordifferent and each is a hydrogen atom, a cycloalkyl group, a group ofthe formula --N(Ra)(Rb) (where Ra and Rb are the same or different andeach is a lower alkyl group or a phenyl group or Ra and Rb may combineto form a lower alkyl-substituted piperazino group) or a lower alkylgroup which may be substituted by hydroxy, lower alkoxy, phenyl,6-membered nitrogen-containing heterocyclic group or a group of theformula --N(Rc)(Rd) (where Rc and Rd are the same or different and eachis a lower alkyl group); R₂ and R₃ may combine to form a cyclicstructure which may optionally include additional oxygen and/or nitrogenatoms and may further have a lower alkyl which may be substituted byhydroxy, or piperidino group, as a substituent; provided, however, thatwhere R₁ is a hydrogen atom, R is --(CH₂)_(m) CHO or --(CH₂)_(n) NR₂ R₃,or a pharmaceutically acceptable salt thereof.

The compound of general formula (I) according to the present inventionhas excellent antitumor activity and is effective in the treatment ofvarious tumors.

Therefore, the invention provides an antitumor composition comprising aneffective amount of a compound of the above general formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The present invention further provides a method of treating tumors inmammalian animals which comprises administering a compound of the abovegeneral formula (I) or a pharmaceutically acceptable salt thereof tomammalian animals.

Referring to the above general formula (I), the lower alkanoyl group R₁includes straight-chain or branched-chain C₂₋₅ alkanoyl groups such asacetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,etc. and the halogen atom may for example be fluorine, chlorine, bromineor iodine. The lower alkyl group, as designated by Rx, Ry, Rz, R₂, R₃,Ra, Rb, Rc and Rd, includes straight-chain or branched-chain C₁₋₆ alkylgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and so on. The loweralkenyl group R includes straight-chain or branched-chain C₂₋₆ alkenylgroups such as vinyl, 1-propenyl, isopropenyl, allyl, 2-butenyl,2-methyl-2-butenyl, 3-pentenyl, 4-hexenyl and so on. The lower alkylgroup having a hydroxy group includes straight-chain or branched-chainC₁₋₆ alkyl groups having 1 or 2 hydroxyl groups, such as hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl,2,3-dihydroxybutyl, 2,3-dihydroxypentyl, 2,3-dihydroxyhexyl and so on.The lower alkyl group having a ketoaldehyde group includes C₁₋ 6 alkylgroups having an 6- or β-ketoaldehyde group, such as2-oxo-2-formyl-1-ethyl, 2-oxo-3-formyl-1-propyl,3-oxo-3-formyl-1-propyl, 3-oxo-4-formyl-1-butyl and so on.

Referring, further, to the above general formula (I), the lower alkoxygroup as represented by R₂ and R₃ includes straight-chain orbranched-chain C₁₋₆ alkoxy groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy and so on. The cycloalkyl group includes C₃₋₆ cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on. The6-membered nitrogen-containing heterocyclic group includes suchheterocyclic groups as pyridyl, piperidino, morpholine and so on. Thecyclic structure which R₂ and R₃ may combinedly form and which mayfurther contain additional oxygen and/or nitrogen atoms includespyrrolidine, piperidine, morpholine, piperazine and so on.

The pharmaceutically acceptable salt of 4-desoxy-4-epipodophyllotoxinderivative according to the present invention includes the correspondingsalts of various organic acids such as formic acid, acetic acid,propionic acid, trifluoroacetic acid, tartaric acid, malic acid, maleicacid, fumaric acid, succinic acid, oxalic acid, etc. and of variousinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid and so on.

The preferred species of the compound of general formula (I) arecompounds in which R₁ is a hydrogen atom or a benzyloxycarbonyl groupand R is a group of the formula --(CH₂)_(n) NR₂ R₃.

The most desirable species are compounds in which R₁ is a hydrogen atomand R is a group of the formula --(CH₂)_(n) NR₂ R₃ wherein n is 2 or 3;R₂ and R₃ are the same or different and each is a hydrogen atom, a groupof the formula --N(Ra)(Rb) (where Ra and Rb are the same or differentand each is a lower alkyl group or Ra and Rb may combine to form a loweralkyl-substituted piperazino group) or a lower alkylgroup which may besubstituted by a 6-membered nitrogen-containing heterocyclic group or agroup of the formula --N(Rc)(Rd) (where Rc and Rd are the same ordifferent and each is a lower alkyl group); or R₂ and R₃ may combine toform a cyclic structure which may include additional oxygen and/ornitrogen atoms and be substituted by a lower alkyl or piperidino group.

The compound of general formula (I) according to the present inventioncan be produced in accordance with the following reaction scheme 1, forinstance. ##STR3##

In the above formulas, R₄ is a methyl group, a benzyloxycarbonyl group,a lower alkanoyl group which may have one or more halogen atoms or agroup of the formula --Si(Rx)(Ry)(Rz) (where Rx, Ry and Rz are asdefined above); R₅ is a lower alkenyl group; R₆ is a hydroxy-containinglower alkyl group; R₇ is a group of the formula --(CH₂)_(m) CHO (where mis as defined above) or a lower alkyl group having a ketoaldehyde group;R₈ is a group of the formula --(CH₂)_(m) CHO; R₉ is a methyl group, abenzyloxycarbonyl group, a lower alkanoyl group which may have a halogenatom or a group of the formula --Si(Rx)(Ry)(Rz) (where Rx, Ry and Rz areas defined above); R₂, R₃ and n are respectively as defined above;provided, however, that R₄ and R₉ are not the same.

Each of the processes shown schematically above is now explained.

Process A

The known 4-epipodophyllotoxin of general formula (II) is reacted with alower alkenylsilane of general formula (III) in the presence of a Lewisacid in an appropriate solvent to give a desired derivative of generalformula (Ia) which corresponds to general formula (I) wherein R is alower alkenyl group. The solvent is not specifically limited insofar asit does not participate in the reaction. Useful solvents include, forexample, aprotic solvents such as halogenated hydrocarbons, e.g.dichloromethane, chloroform, 1,2-dichloroethane, etc. and ethers, e.g.tetrahydrofuran, dioxane, etc. The Lewis acid that may be used includes,for example, titanium tetrachloride, trimethylsilyltrifluoromethane-sulfonate, zinc bromide, boron trifluoride-ethyl etherand so on. For this reaction, the compound of general formula (III) ispreferably used in a proportion of 1 to 5 mol equivalents based on thecompound of general formula (II) and the Lewis acid is preferably usedin a proportion of 0.5 to 3 mol equivalents based on the compound ofgeneral formula (II). The reaction temperature is -100° to 100° C. andpreferably -20° to 20° C.

Process B

The derivative of general formula (Ia) obtained in Process A is oxidizedin an inert solvent to give a desired derivative of general formula (Ib)which corresponds to general formula (I) wherein R is ahydroxy-containing lower alkyl group. As the solvent, carbontetrachloride, acetonitrile, acetic acid, water, pyridine, etc. may beused alone or in combination. The oxidizing agent may for example beruthenium oxide, sodium periodate or osmium tetraoxide. For thisreaction, the oxidizing agent is preferably used in a proportion of 0.1to 2 mol equivalents relative to the compound of general formula (Ia).The reaction temperature is -10° to 80° C. and preferably 0° to 20° C.

Process C

The derivative of general formula (Ia) obtained in Process A issubjected to simultaneous oxidation and reduction in an inert solvent togive a desired derivative of general formula (Ic) which corresponds tosaid general formula (I) wherein R is a group of the formula --(CH₂)_(m)CHO or a lower alkyl group having a ketoaldehyde group. As the solvent,carbon tetrachloride, methylene chloride, acetic acid, water,tetrahydrofuran, pyridine, etc. can be used alone or in combination. Thereducing agent may for example be borane-dimethyl sulfide,thiamylborane-dimethyl sulfide or the like, while the oxidizing agentmay for example be chromic acid or pyridinium chlorochromate. For thisreaction, the reducing agent is preferably used in a proportion of 0.5to 2 mol equivalents and the oxidizing agent in a proportion of 1 to 3mol equivalents, both based on the compound of general formula (Ia). Thereaction temperature is -10° to 50° C. and preferably 0° to 20° C.

Process D

The desired derivative of general formula (Ic) corresponding to generalformula (I) wherein R is a group of the formula --(CH₂)_(m) CHO or alower alkyl group having a ketoaldehyde group can also be obtained byoxidizing in an inert solvent the derivative of general formula (Ib)obtained in Process B. As the solvent, carbon tetrachloride, methylenechloride, acetic acid, tetrahydrofuran, diethyl ether, benzene, etc. canbe used alone or in combination. The oxidizing agent may for example bepotassium permanganate, lead tetraacetate, pyridinium chlorochromate orthe like. For this reaction, the oxidizing agent is preferably used in aproportion of 0.8 to 3 mol equivalents relative to the compound ofgeneral formula (Ib). The reaction temperature is 0° to 50° C. andpreferably 0° to 20° C.

Process E

The derivative of general formula (Ic) obtained in Process C or D iscatalytically reduced in the presence of a catalyst in an inert solventto give a desired derivative of general formula (Id) which correspondsto general formula (I) wherein R is a group of the formula --(CH₂)_(m)CHO. The solvent is not specifically limited insofar as it does notparticipate in the reaction. As the solvent, for example, ethyl acetate,methanol, tetrahydrofuran, etc. can be used alone or in combination. Thecatalyst may for example be palladium black, platinum or the like. Thehydrogen pressure may be 1 to 3 atmospheres and preferably 1 to 2atmospheres. The reaction temperature is 0° to 40° C. and preferablyroom temperature.

Process F

The derivative of general formula (Id) obtained in Process E is reactedwith an acylating agent or a silylating agent in the presence of a basein an inert solvent to give a desired derivative of general formula(Ie). The solvent is not specifically limited insofar as it does notparticipate in the reaction and carbon tetrachloride, methylenechloride, tetrahydrofuran, benzene, dimethylformamide,dimethylacetamide, etc. can be used alone or in combination. The basemay for example be pyridine, dimethylaminopyridine, imidazole or thelike. The acylating agent includes acid anhydrides such as aceticanhydride, propionic anhydride, butyric anhydride, isobutyric anhydride,valeric anhydride, chloroacetic anhydride, etc. and acid halides such asacetyl chloride, propionyl chloride, n-hexanoyl chloride, chloroacetylchloride, dichloroacetyl chloride, trichloroacetyl chloride,benzyloxycarbonyl chloride and so on. The silylating agent includest-butyldimethylsilyl chloride, triisopropylsilyl chloride,t-butyldiphenylsilyl chloride and so on. For this reaction, the base ispreferably used in a proportion of 0.01 to 7 mol equivalents and theacylating agent or the silylating agent is preferably used in aproportion of 1 to 5 mol equivalents, both based on the compound ofgeneral formula (Id). The reaction temperature is 0° to 50° C. andpreferably 0° to 20° C.

Process G

The derivative of general formula (Ic) obtained in Process C or D issubjected to reductive amination with an amino compound of generalformula (IV) in an inert solvent to give a desired derivative of generalformula (If) which corresponds to general formula (I) wherein R is agroup of the formula --(CH₂)_(n) NR₂ R₃. The solvent is not specificallylimited insofar as it does not participate in the reaction. Thus, forexample, alcohols such as methanol, ethanol, etc., ethers such astetrahydrofuran, dioxane, etc., organic acids such as acetic acid,formic acid, etc., water and so on can be used alone or in combination.The reducing agent may for example be sodium borohydride, sodiumcyanoborohydride or the like. For this reaction, the amino compound ofgeneral formula (IV) is preferably used in a proportion of 0.9 to 3 molequivalents and the reducing agent is preferably used in a proportion of1 to 3 mol equivalents, both based on the compound of general formula(Ic). The reaction temperature is 0° to 50° C. and preferably 0° to 20°C.

Process H

The derivative of general formula (If) obtained in Process G iscatalytically reduced in the presence of a catalyst in an inert solventto give a desired derivative of general formula (Ig). The solvent is notparticularly limited insofar as it does not participate in the reaction.Thus, for example, ethyl acetate, methanol, tetrahydrofuran,acetonitrile, etc. can be used alone or in combination. The catalyst mayfor example be palladium black, platinum or the like. The hydrogenpressure may be 1 to 3 atmospheres and preferably 1 to 2 atmospheres.The reaction temperature is 0° to 40° C. and preferably roomtemperature.

The compound of the invention as obtained by any of the above reactionscan be converted to salts by the known procedures, for example byreacting it with said organic acid or inorganic acid in a solvent, suchas methylene chloride, 1,2-dichloroethane, tetrahydrofuran, ethylacetate, etc., at a temperature in the neighborhood of room temperature.

The compounds (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) as obtained inthe above manner can be isolated and purified by the procedures usedcommonly in this technical field, such as concentration, filtration,recrystallization, various types of chromatography and so on.

For use as a therapeutic drug for malignant tumors in mammals includingman, the compound of the present invention can be provided in a varietyof pharmaceutical preparations such as oral preparations, injectablepreparations, suppositories, etc., each of which can be prepared by theestablished pharmaceutical procedure.

In the formulation of solid preparations for oral administration, thecompound of the invention is formulated with an excipient and, whenrequired, a binder, disintegrator, lubricant, coloring agent, corrigent,flavor, etc. and processed into tablets, coated tablets, granules,powders, capsules, etc. in a usual manner. The additives are thosealready used in the art. For example, the excipient includes lactose,sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin,microcrystalline cellulose, silicic acid, etc. The binder includeswater, ethanol, propanol, simple syrup, glucose solution, starchsolution, gelatin solution, carboxymethylcellulose,hydroxypropylcellulose, hydroxypropyl-starch, methylcellulose,ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and soon. The disintegrator includes dried starch, sodium alginate, agarpowder, sodium hydrogen carbonate, calcium carbonate, sodium laurylsulfate, stearyl monoglyceride, lactose and so on. The lubricantincludes purified talc, stearic acid salts, borax, polyethylene glycoland so on. The corrigent includes sucrose, orange peel, citric acid,tartaric acid and so on.

For the formulation of liquid preparations for oral administration, thecompound of the invention can be formulated with a corrigent, buffer,stabilizer, flavor and/or the like and the resulting composition beprocessed into oral solutions, syrups, elixirs, etc. in a usual manner.The corrigent for this purpose may be any of those mentioned above. Thebuffer may for example be sodium citrate and the stabilizer may forexample be tragacantha, gum arabic, gelatin or the like.

For the formulation of injectable preparations, the compound of theinvention can be formulated with a pH adjusting agent, buffer,stabilizer, isotonic agent, local anesthetic, etc. and be processed intoinjections for subcutaneous, intramuscular or intravenous. The pHadjusting agent and buffer that can be used include sodium citrate,sodium acetate, sodium phosphate and so on. The stabilizer includessodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and so on.The local anesthetic includes procaine hydrochloride, lidocainehydrochloride and so on.

For the formulation of suppositories, the compound of the invention canbe formulated with a pharmaceutical carrier well known in the art, suchas polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride,Witepsol (trademark), etc. and, where necessary, with a surfactant suchas Tween (trademark) and the resulting composition be processed intosuppositories in a usual manner.

The amount of the compound of the present invention in any of theabove-mentioned unit dosage forms depends on the clinical condition ofthe patient to be treated and the particular dosage form selected.Generally, however, the preferred amount per dosage unit is about 1 to1000 mg for oral preparations, about 0.1 to 500 mg for injections andabout 5 to 1000 mg for suppositories. The daily dosage of anypharmaceutical preparation mentioned above is also dependent on thepatient's condition, body weight, age, sex and other factors but it isgenerally recommendable to administer about 0.1 to 5000 mg, preferably 1to 1000 mg, per day for an adult patient, either in a single dose or in2 to 4 divided doses.

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples, pharmacological tests and preparation examplesare further illustrative of the invention.

EXAMPLE 1

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin(Compound 1)

To a solution of 1 g (1.87 mmol) of4'-demethyl-4'-O-benzyloxycarbonyl-4-epipodophyllotoxin in 15 ml ofdichloromethane was added 426 mg (3.73 mmol) of trimethylallylsilane andthe mixture was cooled to -10°-0° C. To this solution was added 0.6 mlof boron trifluoride ethyl ether and the mixture was stirred for 1 hour.After the reaction, 0.6 ml of pyridine was added and the mixture waspoured in cold diluted hydrochloric acid and extracted with ethylacetate. The organic layer was dried and distilled and the residue waspurified by column chromatography (silica 50 g, eluent: chloroform). Theeluate was concentrated and crystallized from ether to give 1 g (yield95.7 %) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin(Compound 1).

m.p.: 135°-137° C., [α]²⁰ _(D) =-70.03° (c=1.30, DMSO), ¹ H-NMR (CDCl₃)δppm: 7.30-7.43 (5H, m, --OCOOCH₂ Ph), 6.72 (1H, s, 5-H), 6.46 (1H, s,8-H), 6.31 (2H, s, 2'-H, 6'-H), 5.94 (1H, d, J=1.5 Hz, --OCH₂ O--), 5.93(1H, d, J=1.5 Hz, --OCH₂ O--), 5.80 (1H, d-d-t, J=17, 10.5, 6.5 Hz,--CH₂ CH=CH₂), 5.25 (2H, s, --OCOOCH₂ Ph), 5.12 (1H, d-d-t, J=17, 2, 1.5Hz, --CH₂ CH=CH₂), 5.11 (1H, d-q, J=10.5, 1.5 Hz, --CH₂ CH=CH₂), 4.58(1H, d, J=5 Hz, 1-H), 4.25 (2H, m, 11-H), 3.68 (6H, s, 3'-OCH₃,5'-OCH₃), 3.27 (1H, m, 4-H), 3.07 (1H, d-d, J=14.5, 5 Hz, 2-H), 2.93(1H, m, 3-H), 2.57 (1H, m, --CH₂ CH=CH₂), 2.42 (1H, m, --CH₂ CH=CH₂)

EXAMPLE 2

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin(Compound 2)

To a solution of 1 g (1.79 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin,obtained in Example 1, in 2 ml of pyridine was added 455 mg (1.79 mmol)of osmium tetraoxide and the mixture was stirred at room temperature for1 hour. Following this reaction, a solution of 0.8 g of sodiumhydrogensulfite in aqueous pyridine was added and the mixture wasfurther stirred for 30 minutes. The reaction mixture was extracted withethyl acetate and the extract was washed with diluted hydrochloric acidand water and dried. The organic layer was concentrated and the residuewas purified by column chromatography (silica 50 g, eluent:chloroform-methanol=20:1). The eluate was concentrated and the residuewas crystallized from ether to give 1.0 g (yield 94.2%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin(Compound 2).

m.p.: 170.5°-172° C., [a]²⁰ _(D) =-62.25° (c=0.66, DMSO), ¹ H-NMR(DMSO-d₆) δppm: 7.40 (5H, s, --OCOOCH₂ Ph), 6.94, 6.84 (1H, s, 5-H),6.44 (1H, s, 8-H), 6.34, 6.32 (2H, s, 2'-H, 6'-H), 5.96 (2H, s, --OCH₂O--), 5.23 (2H, s, --OCOOCH₂ Ph), 4.78 (1H, m, --CH₂ CH(OH)CH₂ OH), 4.58(1H, d, J=6.0 Hz, 1-H), 4.52 (1H, m, --CH₂ CH(OH)CH₂ OH), 4.35 (1H, m,11α-H), 4.17 (1H, m, 11β-H), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.17-3.69(4H, m, --CH₂ CH(OH)CH₂ OH, 4 -H), 2.94-3.02 (1H, m, 2-H), 2.19 (1H, m,3-H), 1.67 (1H, --CH₂ CH(OH)CH₂ OH), 1.24-1.32 (1H, m, --CH₂ CH(OH)CH₂OH)

EXAMPLE 3

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin(Compound 3)

To a solution of 1 g (1.69 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin,obtained in Example 2, in 80 ml of benzene was added 795 mg (1.79 mmol)of lead tetraacetate and the mixture was stirred at room temperature for30 minutes. The reaction mixture was then filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (silica70 g, eluent: chloroform-methanol=20:1) and crystallized from ether togive 934 mg (yield 98.7%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin(Compound 3).

m.p.: 180°-182° C., [α]²⁰ _(D) =-71.04° (c=1.32, DMSO), ¹ H-NMR(DMSO-d₆) δppm: 9.73 (1H, s, --CHO), 7.39 (5H, s, --OCOOCH₂ Ph), 6.88(1H, s, 5-H), 6.46 (1H, s, 8-H), 6.35 (2H, s, 2'-H, 6'-H), 5.96 (2H, s,--OCH₂ --), 5.23 (2H, s, --OCOOCH₂ Ph), 4.54 (1H, d, J=3.6 Hz, 1-H),3.96-4.32 (1H, m, 11α-H), 3.63 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.48-3.92 (1H,m, 11α-H), 2.56-3.40 (5H, m, 2-H, 3-H, 4-H, --CH₂ CHO)

EXAMPLE 4

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-formyl-1-ethyl)-4-epipodophyllotoxin(Compound 4)

To a solution of 4 g (7.17 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin,obtained in Example 1, in 40 ml of tetrahydrofuran was added 4.3 ml (8.6mmol) of a 2M solution of boran-dimethyl sulfide in tetrahydrofurandropwise with ice-cooling and the mixture was then reacted at roomtemperature for 1 hour. The reaction mixture was concentrated and theresidue was dissolved in 80 ml of methylene chloride followed byaddition of 3.0 g (13.9 mmol) of pyridinium chlorochromate. The mixturewas stirred at room temperature. After the reaction, 100 ml of ethylacetate was added and the insoluble matter was filtered off with the aidof Florisil. The filtrate was concentrated and the residue was purifiedby column chromatography (silica 50 g, eluent: hexane-ethyl acetate=1:1)and crystallized from ether to give 1.85 g (yield 44.9%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-formyl-1-ethyl)-4-epipodophyllotoxin(Compound 4).

m.p.: 153°-155° C., [α]²⁰ _(D) =-69.09° (c=0.38, DMSO), ¹ H-NMR (CDCl₃)δppm: 9.83 (1H, s, --CHO), 7.40 (5H, m, --OCOOCH₂ ph), 6.83 (1H, s,5-H), 6.45 (1H, s, 8-H), 6.28 (2H, s, 2'-H, 6'-H), 5.94 (2H, s, --OCH₂O--), 5.25 (2H, s, --OCOOCH₂ Ph), 4.58 (1H, d, J=4.6 Hz, 1-H), 4.37 (1H,m, 11α-H), 4.11 (1H, m, 11β-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃),3.04-3.10 (1H, m, 4-H), 2.86-3.00 (2H, m, 2-H, 3-H), 2.49-2.67 (2H, m,-- CH₂ CHO), 1.83-2.21 (2H, m, --CH₂ CH₂ CHO)

EXAMPLE 5

Synthesis of 4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin(Compound 5)

To a solution of 100 mg (0.178 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin,obtained in Example 3, in 10 ml of ethyl acetate-methanol (1:1) wasadded 30 mg of 5% palladium-on-carbon, and catalytic reduction wascarried out in hydrogen streams (at atmospheric pressure). Followingthis reaction, the 5% palladium-on-carbon was filtered off and thefiltrate was concentrated under reduced pressure. The residue wascrystallized from ether to give 75 mg (yield 98.9%) of4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin (Compound 5).

m.p.: 237°-239° C., [α]²⁰ _(D) =-110.12° (c=0.38, DMSO) ¹ H-NMR (CDCl₃ )δppm: 9.72 (1H, s, --CHO), 8.22 (1H, s, 4'-OH), 6.86 (1H, s, 5-H), 6.43(1H, s, 8-H), 6.21 (2H, s, 2'-H, 6'-H), 5.96, 5.94 (2H, s, --OCH₂ O--),4.41 (1H, d, J=5.28 Hz, 1-H), 4.15 (1H, d-d, J=7.9, 3.9 Hz, 11α-H),3.66-3.73 (1H, m, 11β-H), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.56-3.40 (5H,m, 2-H, 3-H, 4-H, --CH₂ CHO)

EXAMPLE 6

Synthesis of 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-oxo-2-formyl-1-ethyl)-4-epipodophyllotoxin (Compound 6)

To a solution of 100 mg (0.17 mmol) of 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin,prepared in Example 2, in 5 ml of methylene chloride was added 73 mg(0.34 mmol) of pyridinium chlorochromate and the mixture was stirred atroom temperature for 1 hour. After the reaction, ethyl acetate was addedand the organic layer was washed with cold diluted hydrochloric acid andsaturated aqueous sodium chloride solution and dried over magnesiumsulfate. The solvent was distilled off and the residue was purified bycolumn chromatography (silica 20 g, eluent: chloroform-methanol=20:1)and crystallized from ether to give 45 mg (yield 45.0%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-oxo-2-formyl-1-ethyl)-4-epipodophyllotoxin(Compound 6).

¹ H-NMR (CDCl₃) δppm: 9.85 (1H, s, --CH₂ COCHO), 7.38 (5H, m, --OCOOCH₂Ph), 6.61 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.31 (2H, s, 2'-H, 6'-H),5.93 (2H, s, --OCH₂ O--), 5.25 (2H, s, --OCOOCH₂ Ph), 4.55 (1H, d, J=3.6Hz, 1-H), 4.12-4.40 (1H, m, 11α-H), 3.48-4.00 (1H, m, 11β-H), 3.68 (6H,s, 3'-OCH₃, 5'-OCH₃), 2.60-3.08 (5H, m, 2-H, 3-H, 4-H, --CH₂ COCHO)

EXAMPLE 7

Synthesis of4-desoxy-4'-demethyl-4'-O-chloroacetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 7)

To a solution of 50 mg (0,117 mmol) of4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin, obtained inExample 5, in 5 ml of tetrahydrofuran were added 50 mg (0,292 mmol) ofchloroacetic anhydride and 10 mg (0.081 mmol) of dimethylaminopyridineand the mixture was stirred at room temperature overnight. After thereaction, the solvent was distilled off and the residue was purified bypreparative thin-layer chromatography (eluent:chloroform-methanol=30:1). The residue obtained by extraction wascrystallized from ethyl acetate-n-hexane and the crystals were collectedby filtration to give 50 mg (yield 90.0%) of4-desoxy-4'-demethyl-4'-O-chloroacetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 7).

m.p.: 119°-121° C., [α]²⁰ _(D) =-85.21° (c=0.399, DMSO), ¹ H-NMR (CDCl₃)δppm: 9.64 (1H, s, --CHO), 6.40 (1H, s, 5-H), 6.25 (1H, s, 8-H), 6.10(2H, s, 2'-H, 6'-H), 5.73 (1H, s, --OCH₂ O--), 5.72 (1H, s, --OCH₂ O--),4.36 (1H, d, J=4.9 Hz, 1-H), 4.12 (2H, s, ClCH₂ CO--), 4.06 (1H, d,J=7.2 Hz, 11α-H), 3.61 (1H, m, 11β-H), 3.46 (6H, s, 3'-OCH₃, 5'-OCH₃),3.37 (1H, t, J=10.5 Hz, 2-H), 2.51-2.85 (4H, m, 3-H, 4-H, --CH₂ CHO)

EXAMPLE 8

Synthesis of4-desoxy-4'-demethyl-4'-O-trichloroacetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 8)

To a solution of 4.26 g (10 mmol) of4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin, obtained inExample 5, in 50 ml of methylene chloride were added 2.36 g (13 mmol) oftrichloroacetyl chloride and 1.58 g (13 mmol) of dimethylaminopyridineand the mixture was stirred at room temperature overnight. After thereaction, the solvent was distilled off and the residue was purified bycolumn chromatography (eluent: ethyl acetate-n-hexane =1:1). The eluatewas crystallized from methanol and the crystals were collected byfiltration to give 4.10 g (yield 71.7%) of4-desoxy-4'-demethyl-4'-0-trichloroacetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 8).

m.p.: 177°-178° C., [α]²⁰ _(D) =-68.96° (c=0.58, DMSO), ¹ H-NMR (CDCl₃)δppm: 9.88 (1H, s, --CHO), 6.63 (1H, s, 5-H), 6.47 (1H, s, 8-H), 6.35(2H, s, 2'-H, 6'-H), 5.96 (1H, s, --OCH₂ O--), 4.61 (1H, d, J=5.2 Hz,1-H), 4.30 (1H, t, J=8.9 Hz, 11α-H), 3.80 (1H, m, 11β-H), 3.72 (6H, s,3'-OCH₃, 5'-OCH₃), 3.60 (1H, t, J=9.6 Hz, 2-H), 2.70-3.10 (4H, m, 3-H,4-H, --CH₂ CHO)

EXAMPLE 9

Synthesis of4-desoxy-4'-demethyl-4'-O-acetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 9)

To a solution of 50 mg (0.117 mmol) of4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin, obtained inExample 5, in 5 ml of tetrahydrofuran were added 50 mg (0.49 mmol) ofacetic anhydride and 10 mg (0.081 mmol) of dimethylaminopyridine and themixture was stirred at room temperature overnight. After the reaction,the solvent was distilled off and the residue was purified bypreparative thin-layer chromatography (eluent:chloroform-methanol=30:1). The residue obtained by extraction wascrystallized from n-hexane and the crystals were collected by filtrationto give 40 mg (yield 73.0%) of4-desoxy-4'-demethyl-4'-O-acetyl-4-formylmethyl-4-epipodophyllotoxin(Compound 9).

m.p.: 130°-133° C., [α]²⁰ _(D) =-88.40° (c=0.5, DMSO) ¹ H-NMR (CDCl₃)δppm: 9.55 (1H, s, --CHO), 6.30 (1H, s, 5-H), 6.16 (1H, s, 8-H), 5.99(2H, s, 2'-H, 6'-H), 5.63 (1H, s, --OCH₂ O--), 5.62 (1H, s, --OCH₂ O--),4.27 (1H, d, J=4.9 Hz, 1-H), 3.98 (1H, t, J=8.2 Hz, 11α-H), 3.51 (1H, m,11β-H), 3.37 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.28 (1H, t, J=9.9 Hz, 2-H),2.42-2.75 (4H, m, 3-H, 4-H, --CH₂ CHO), 1.97 (3H, s, --OCOCH₃)

EXAMPLE 10

Synthesis of4-desoxy-4'-demethyl-4'-O-t-butyldiphenylsilyl-4-formylmethyl-4-epipodophyllotoxin(Compound 10)

To a solution of 50 mg (0.117 mmol) of4-desoxy-4'-demethyl-4-formylmethyl-4-epipodophyllotoxin, obtained inExample 5, in 5 ml of dimethylformamide were added 33 mg (0.12 mmol) oft-butyldiphenylsilyl chloride and 79 mg (0.64 mmol) ofdimethylaminopyridine and the mixture was stirred at room temperatureovernight. The reaction mixture was then extracted with ethylacetate-water and dried. The solvent was then distilled off and theresidue was purified by preparative thin-layer chromatography (eluent:chloroform-methanol=30:1). The residue obtained by extraction was driedunder reduced pressure to give 35 mg (yield 37.4%) of4-desoxy-4'-demethyl-4'-O-t-butyldiphenylsilyl-4-formylmethyl-4-epipodophyllotoxin(Compound 10 ).

¹ H-NMR (CDCl₃) δppm: 9.71 (1H, s, (--CHO), 7.71 ##STR4## 6.50 (1H, s,5-H), 6.38 (1H, s, 8-H), 6.06 (2H, s, 2'-H, 6'-H), 5.87 (2H, s, --OCH₂O), 4.40 (1H, d, J=4.9 Hz, 1-H), 4.16 (1H, t, J=7.5 Hz, 11α-H), 3.70(1H, m, 11β-H), 3.43 (1H, t, J=9.5 Hz, 2-H), 3.28 (6H, s, 3'-OCH₃,5'-OCH₃), 2.47-2.84 (4H, m, 3-H, 4-H, --CH₂ CHO), 1.05 (9H, s, -Si-t-Bu)

EXAMPLE 11

Synthesis of 4-desoxy-4-formylmethyl-4-epipodophyllotoxin (Compound 11)

To a solution of 500 mg (1.2 mmol) of 4-epipodophyllotoxin in 10 ml ofdichloromethane was added 274 mg (2.4 mmol) of trimethylallylsilane andthe mixture was cooled to -10°-0° C. To this solution was added 0.35 mlof boron trifluoride ethyl ether and the mixture was stirred for 4hours. After 0.35 ml of pyridine was added, the reaction mixture wasextracted with ethyl acetate. The organic layer was dried and distilledand the residue was purified by column chromatography (silica 50 g,eluent: ethyl acetate-hexane=1:2). The eluate was crystallized fromether-hexane and the crystals were collected by filtration to give 450mg (yield 81.1%) of 4-desoxy-4-allyl-4-epipodophyllotoxin. Then, to asolution of 200 mg (0.46 mmol) of this compound in pyridine (4 ml) wasadded 116 mg (0.46 mmol) of osmium tetraoxide and the mixture wasstirred at room temperature for 1 hour. After the reaction, a solutionof 0.1 g of sodium hydrogensulfite in aqueous pyridine was added and themixture was stirred for 30 minutes. This reaction mixture was extractedwith ethyl acetate and the extract was washed with diluted hydrochloricacid and water and dried. The organic layer was concentrated and theresidue was purified by column chromatography (silica 50 g, eluent:chloroform-methanol=20:1). The eluate was concentrated and, then,crystallized from ether-hexane to give 194 mg (yield 89.3%) of4-desoxy-4-(2,3-dihydroxy-1-propyl)-4-epipodophyllotoxin.

m.p.: 144°-145° C., [α]²⁰ _(D) =-73.42° (c=0.52, CHCl₃)

Then, to a solution of 100 mg (0.21 mmol) of this compound in 10 ml ofbenzene was added 113 mg (0.25 mmol) of lead tetraacetate and themixture was stirred at room temperature for 20 minutes. The reactionmixture was then filtered and the filtrate was concentrated. The residuewas purified by column chromatography (silica 20 g, eluent:chloroform-methanol=20:1) and crystallized from ether-hexane (1:1) togive 90 mg (yield 97.4%) of 4-desoxy-4-formylmethyl-4-epipodophyllotoxin(Compound 11).

m.p.: 157°-159° C., [α]²⁰ _(D) =-105.82° (c=1.253, DMSO), ¹ H-NMR(CDCl₃) δppm: 9.84 (1H, s, --CHO), 6.29 (1H, s, 5-H), 6.46 (1H, s, 8-H),6.28 (2H, s, 2'-H, 6'-H), 5.93 (2H, s, --OCH₂ O--), 4.52 (1H, d, J=3.6Hz, 1-H), 4.12-4.36 (1H, m, 11α-H), 3.79 (3H, s, 4'-OCH₃), 3.74 (6H, s,3'-OCH₃, 5'-OCH₃), 3.40-3.92 (1H, m, 11β-H), 2.56-3.24 (5H, m, 2-H, 3-H,4-H, --CH₂ CHO)

EXAMPLE 12

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-propyl)-4-epipodophyllotoxin(Compound 12)

To a mixture of 0.1 ml of 50% aqueous solution of dimethylamine and 3 mlof methanol were added 0.1 ml of acetic acid and 35 mg (0.56 mmol) ofsodium cyanoborohydride, followed by addition of 300 mg (0.52 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-formyl-1-ethyl)-4-epipodophyllotoxinobtained in Example 4. The mixture was reacted at room temperature for 1hour. Then, after 30 ml of chloroform was added, the reaction mixturewas washed with saturated aqueous sodium hydrogen carbonate solution andwater and dried over magnesium sulfate. The solvent was then distilledoff and the residue was purified by column chromatography (silica 20 g,eluent: chloroform-methanol=20:1) to give 245 mg (yield 78%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-propyl)-4-epipodophyllotoxin(Compound 12).

EXAMPLE 13

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-ethyl)-4-epipodophyllotoxin(Compound 13)

To a mixture of 15 mg (0.167 mmol) of 50% aqueous solution ofdimethylamine and 5 ml of methanol were added 0.1 ml of acetic acid and10 mg (0.19 mmol) of sodium cyanoborohydride, followed by addition of100 mg (0.178 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxinobtained in Example 3, and the mixture was reacted at room temperaturefor 1 hour. Then, after 100 ml of ethyl acetate was added, the reactionmixture was washed with saturated aqueous sodium hydrogen carbonatesolution and water and dried over magnesium sulfate. The solvent wasthen distilled off and the residue was purified by thin-layerchromatography (eluent: chloroform-methanol=5:1) to give 60 mg (yield57.2%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-ethyl)-4epipodophyllotoxin(Compound 13).

EXAMPLE 14

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-N-methyl-N-cyclohexylamino-1-ethyl)-4-epipodophyllotoxin(Compound 14)

To a solution of 180 mg (1.81 mmol) of cyclohexylamine in 10 ml ofmethanol were added 0.1 ml of acetic acid and 85 mg (1.35 mmol) ofsodium cyanoborohydride followed by addition of 500 mg (0.9 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxinobtained in Example 3, and the mixture was reacted at room temperaturefor 1 hour. To this reaction mixture was added 0.1 ml of 37% formalinand the reaction was further allowed to proceed at room temperature for1 hour. The reaction mixture was diluted with chloroform, washed withsaturated aqueous sodium hydrogen carbonate solution and water and driedover magnesium sulfate. The solvent was then distilled off and theresidue was purified by column chromatography (silica 20 g, eluent:chloroform-methanol=20:1) to give 470 mg (yield 79%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-N-methyl-N-cyclohexylamino-1-ethyl)-4-epipodophyllotoxin(Compound 14).

EXAMPLE 15

Synthesis of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-N,N-diethylamino-1-ethyl)-4-epipodophyllotoxin(Compound 15)

To a mixture of 38 mg (0.53 mmol) of diethylamine and 10 ml of methanolwere added 0.1 ml of acetic acid and 52 mg (0.82 mmol) of sodiumcyanoborohydride followed by addition of 300 mg (0.53 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxinobtained in Example 3, and the mixture was reacted at room temperaturefor 1 hour. This reaction mixture was diluted with chloroform, washedwith saturated aqueous sodium hydrogen carbonate solution and water anddried over magnesium sulfate. The solvent was then distilled off and theresidue was purified by column chromatography (silica 20 g, eluent:chloroform-methanol=20:1) to give 175 mg (yield 53.5%) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-N,N-diethylamino-1-ethyl)-4-epipodophyllotoxin(Compound 15).

EXAMPLE 16 THROUGH 27

Compounds 16 through 27, shown in Table 1, were synthesized in the samemanner as Examples 12 through 15.

                  TABLE 1                                                         ______________________________________                                         ##STR5##                                                                     ______________________________________                                    

Compound: 12

R=-CH₂ CH₂ CH₂ N(CH₃)₂, Yield: 78.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm),7.37 (5H, m, PhCH₂ OCO--), 6.71 (1H, s, 5-H) , 6.44 (1H, s, 8-H), 6.30(2H, s, 2'-H, 6'-H), 5.93 (2H, s, --OCH₂ --), 5.25 (2H, s, PhCH₂ OCO--),4.00-4.60 (3H, m, 1-H, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.00 (3H,m, 2-H, 3-H, 4-H), 2.20-2.40 (2H, m, --CH₂ N<) , 2.22 (6H, s,--N(CH₃)₂), 1.66 (4H, m, --CH₂ CH₂ CH₂ N<)

Compound: 13

R=-CH₂ CH₂ N(CH₃)₂, Yield: 57.2%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm),7.37 (5H, m, PhCH₂ OCO--), 6.74 (1H, s, 5-H) , 6.44 (1H, s, 8-H), 6.29(2H, s, 2'-H, 6'-H), 5.93 (2H, s, --OCH₂ --), 5.25 (2H, s, PhCH₂ OCO--),4.56 (1H, d, J=5.5 Hz, 1-H), 4.00-4.28 (2H, m, 11-H), 3.67 (6H, s,3'-OCH₃, 5'-OCH₃), 2.68-3.28 (3H, m, 2-H, 3-H, 4-H), 2.32 (2H, t, J=7.2Hz, --CH₂ N<) 2.27 (6H, s, --N(CH₃)₂), 1.48-2.04 (2H, m, --CH₂ CH₂ N<)

Compound: 14 ##STR6##

Yield: 79.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.46 (5H, m, PhCH₂OCO--), 6.73 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.31 (2H, s, 2'-H, 6'-H),5.93 (2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂ OCO--), 4.10-4.60 (3H, m,1-H, 11-H), 3.68 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.80-3.16 (3H, m, 2-H, 3-H,4-H), 2.38-2.53 ##STR7## 2.26 (3H, s, >NCH₃), 1.79 ##STR8##

Compound: 15

R=-CH₂ CH₂ N(C₂ H₅)₂, Yield: 53.5%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm)7.45 (5H, m, PhCH₂ OCO--), 6.65 (1H, s, 5-H), 6.38 (1H, s, 8-H), 6.28(2H, s, 2'-H, 6'-H), 5.86 (1H, d, J=1.5 Hz, --OCH₂ O--), 5.85 (1H, d,J=1.5 Hz, --OCH₂ O--), 5.26 (2H, s, PhCH₂ OCO--), 4.47 (1H, d, J=5.0 Hz,1-H), 4.26 (1H, dd, J=9.7 Hz, 11α-H), 4.06 (1H, t, J=9 Hz, 11β-H), 3.71(6H, s, 3'-OCH₃, 5'-OCH₃), 3.06 (1H, dt, J=7 Hz, 5 Hz, 4-H), 2.91 (1H,dd, J=14 Hz, 5 Hz, 2-H), 2.87 (1 H, dddd, J=14 Hz, 9 Hz, 7 Hz, 5 Hz,3-H), 2.49 (4H, q, J=7 Hz, --N(CH₂ CH₃)₂), 2.41 (2H, m, --CH₂ CH₂ N<),1.82 (1H, m, --CH₂ CH₂ N<), 1.63 (1H, m, --CH₂ CH₂ N<), 0.98 (6H, t, J=7Hz, --N(CH₂ CH₃)₂)

Compound: 16 ##STR9##

Yield: 79.5%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.37 (5H, m, PhCH₂OCO--), 6.72 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.30 (2H, s, 2'-H,6'-H),5.93 (2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂ OCO--), 4.00-4.60(3H, m, 1-H, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.80-3.20 (5H, m,2-H, 3-H, 4-H, --CH₂ OH) , 2.40-2.70 (4H, m, --CH₂ NCH₂ --), 2.30 (3H,s, >NCH₃), 1.60-2.10 (2H, m, --CH₂ CH₂ N<)

Compound: 17 ##STR10##

Yield: 79.9%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.37 (5H, m, PhCH₂OCO--), 6.79 (1H, s, 5-H), 6.43 (1H, s, 8-H), 6.31 (2H, s, 2'-H,6'-H),5.92 (2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂ OCO--), 4.54 (1H,J=5.5 Hz, 1-H), 4.10-4.40 (2H, m, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃),2.80-3.30 (3H, m, 2-H, 3-H, 4-H), 2.46 (2H, t, J=7.2 Hz, --CH₂ N<) 2.33(6H s, -N(CH₃)₂), 2.26(3H, s, --N (CH₃)-N(CH₃)₂), 1.60-2.10 (2H, m,--CH₂ CH₂ N<)

Compound: 18 ##STR11##

Yield: 76.9%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.37 (5H, m, PhCH₂OCO--), 6.74 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.29 (2H, s, 2'-H, 6'-H),5.92 (2H, s, --OCH₂ O--), 5.24 (2H, s, PhCH₂ OCO--), 4.56 (1H, d, J=5.4Hz, 1-H), 3.96-4.44 (2H, m, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃),2.76-3.28 (3H, m, 2-H, 3-H, 4-H), 2.49 ##STR12## 2.30 (3H, s, >NCH₃),2.36 ##STR13## 2.08 ##STR14##

Compound: 19 ##STR15##

Yield: 42.4%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.38 (5H, m, PhCH₂OCO--), 6.75 (1H, s, 5-H), 6.44 (1H, s, 8-H) , 6.30 (2H, s, 2'-H, 6'-H),5.93 (2H, s, --OCH₂ O--) , 5.25 (2H, s, PhCH₂ OCO--), 4.56 (1H, d, J=4.5Hz, 1-H ) , 3.96-4.40 (2H, m, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃),2.80-3.24 (3H, m, 2-H, 3-H, 4-H), 2.38-2.60 (6H, m, --CH₂ NCH₂ CH₂ N<),2.27 (9H, s, --N(CH₃)CH₂ CH₂ N(CH₃)₂, 1.60-2.08 (2H, m --CH₂ CH₂N(CH.sub. 3)CH₂ CH₂ N<)

Compound: 20 ##STR16##

Yield: 70.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.37 (5H, PhCH₂ OCO--),6.68 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.30 (2H, s, 2'-H, 6'-H), 5.93(2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂ OCO--), 4.59 (1H, d, J=3.6 Hz,1-H), 3.92-4.48 (2H, m, 11-H), 3.68 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.66 (4H,d, J=7.0 Hz, --CH(CH₂ OH)₂), 2.60-3.24 (7H, m, 2-H, 3-H, 4 -H, --CH₂NCH<), 2.37 (3H, s, >NCH₃), 1.48-2.20 (4H, b, --CH₂ CH₂ NCH(CH₂ OH)₂)

Compound: 21 ##STR17##

Yield: 64.0%, ¹ H-NMR [Solvent: CDCl₃ : δ(ppm), 7.37 (5H, m, PhCH₂OCO--), 6.74 (s, 5-H), 6.44 (1H, s, 8-H), 6.30 (2H, s, 2'-H, 6'-H), 5.93(2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂ OCO--), 4.00-4.60 (3H, m, 1-H,11-H), 3.55 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.90-3.20 ##STR18## 2.43-2.55##STR19## 2.27 (3H, s, >NCH₃), 1.40-1.76 ##STR20##

Compound: 22 ##STR21## Yield: 96.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm),7.38 (5H, m, PhCH₂ OCO--), 6.75 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.30(2H, s, 2'-H, 6'-H) , 5.93 (2H, s, --OCH₂ O--), 5.25 (2H, s, PhCH₂OCO--), 4.24-4.55 (3H, m, 1-H, 11-H), 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃),2.90-3.44 (3H, m, 2-H, 3-H, 4-H), 2.24-2.40 ##STR22## 1.20-1.95##STR23## Compound: 23 ##STR24## Yield: 79.1%, ¹ H-NMR [Solvent: DMSO-d₆]: δ(ppm), 7.39 (5H, m, PhCH₂ OCO--), 7.02 (1H, s, 5-H), 6.48 (1H, s,8-H), 6.32 (2H, s, 2'-H, 6'-H), 5.98 (2H, s, --OCH₂ O--), 5.23 (2H, s,PhCH₂ OCO--), 4.54 (1H, d, J=3.6 Hz, 1-H), 3.92-4.44 (2H, 11-H), 3.62(6H, s, 3'-OCH₃, 5'-OCH₃), 2.60-3.50 ##STR25## Compound: 24 ##STR26##Yield: 76.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm), 7.38 (5H, m, PhCH₂OCO--), 6.80 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.30 (2H, s, 2'-H, 6'-H),5.93 (2H, s, --OCH₂ O--), 5.26 (2H, s, PhCH₂ OCO--), 4.57(1H, d, J=5.0Hz, 1-H) , 4.34 (1H, t, J=9.6 Hz, 11α-H), 4.14 (1H, t, J=9.5 Hz, 11β-H),3.68 (6H, S, 3'-OCH₃, 5'OCH₃), 3.53 (2H, t, J=5.0 Hz, --CH₂ OCH₃), 3.39(1H, m, 4-H), 3.37 (3H, s, --CH₂ OCH₃), 2.95-3.19 (2H, m, 2-H, 3-H),2.64 (2H, m, --CH₂ N<), 2.48 (2H, m, >NCH₂ CH₂ OCH₃), 2.34 (3H, s,>NCH₃), 1.96 (1H, m, --CH₂ CH₂ N<), 1.72 (1H, m, --CH₂ CH₂ N<) Compound:25 ##STR27## Yield: 65.0%, ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 8.51##STR28## 7.39 (5H, m, PhCH₂ OCO--), 7.34 ##STR29## 6.82 (1H, s, 5-H),6.45 (1H, s, 8-H), 6.32 (2H, s, 2'-H, 6'-H), 5.96 (2H, s, --OCH₂ O--),5.23 (2H, s, PhCH₂ OCO--), 4.52 (1h, d, J=5.9 Hz, 1-H), 4.26 (1H, m,11α-H), 4.05 (1H, m, 11β-H), 3.10-3.70 ##STR30## 3.62 (6H, s, 3'-OCH₃,5'-OCH-₃), 2.90 (1H, m, 3-H), 2.30-2.50 (2H, m, --CH₂ CH₂ N<), 2.16 (3H,s, >NCH₃), 2.10 (1H, m, --CH₂ CH₂ N<), 1.60 (1H, m, --CH₂ CH₂ N<)Compound: 26 ##STR31## Yield: 66.0%, ¹ H-NMR [Solvent: CDCl₃ ]: δ(ppm)8.57 ##STR32## 6.74 (1H, s, 5-H), 6.43 (1H, s, 8-H), 6.29 (2H, s, 2'-H,6'-H), 5.93, 5.92 (2H, d×2, J=1 Hz, --OCH₂ O--), 5.25 (2H, s, PhCH₂OCO--), 4.55 (1H, d, J=5 Hz, 1-H), 4.10 (1H, m, 11α-H), 4.00 (1H, m,11β-H), 3.73 ##STR33## 3.67 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.15 (1H, m,4-H), 2.97 (1H, dd, J=5.3 Hz, 9.8 Hz, 2-H), 2.87 (1H, m, 3-H), 2.44 (2H,m, --CH₂ CH₂ N<), 2.34 (3H, s, >NCH₃), 1.91 (1H, m, --CH₂ CH₂ N<), 1.78(1H, m, --CH₂ CH₂ N<) Compound: 27 ##STR34## Yield: 58.0%, ¹ H-NMR[Solvent: CDCl₃ ]: δ(ppm), 7.46 (5H, m, PhCH₂ OCO--), 6.75 (1H, s, 5-H),6.44 (1H, s, 8-H, 6.30 (2H, s, 2'-H, 6'-H), 5.94 (2H, s, --OCH₂ O--),5.25 (2H, s, PhCH₂ OCO--), 4.57 (1H, d, J=5 Hz, 1-H) , 4.35 (1H, t,J=7.7 Hz, 11α-H), 4.13 (1H, t, J=8.5 Hz , 11β-H) , 3.68 (6H, s, 3'-OCH₃,5'-OCH₃), 3.16 (1H, m, 4-H), 3.02 (1H, dd, J=5 Hz, 8.5 Hz, 2-H), 2.92(1H, m, 3-H), 2.38 (6H, m, --CH₂ NCH₂ CH₂ CH₂ N(CH₃)₂), 2.27 (6H, s,--N(CH₃)₂), 2.24 (3H, s, --N(CH₃)-CH₂ --), 1.68-2.07 (4H, m, --CH₂ CH₂N-CH₂ CH₂ CH₂ N(CH₃)₂) EXAMPLE 28

Synthesis of4-desoxy-4'-demethyl-4-(3-N,N-di-methylamino-1-propyl)-4-epipodophyllotoxin(Compound 28)

To a solution of 230 mg (0.38 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(3-N,N-dimethylamino-1-propyl)-4-epipodophyllotoxin,obtained in Example 12, in 4 ml of ethyl acetate-methanol (1:1) wasadded 50 mg of 10% palladium-on-carbon and the mixture was reacted atroom temperature in hydrogen streams at atmospheric pressure for 4hours. After the catalyst was filtered off, the solvent was distilledoff and the residue was purified by column chromatography (silica 5 g,eluent: chloroform-methanol=20:1). The eluate was dissolved in 2 ml ofdichloroethane followed by addition of 0.2 ml of 4N-HCl-ethyl acetate.The mixture was concentrated under reduced pressure and the residue wascrystallized from diethyl ether to give 110 mg (yield 61.5%) of4-desoxy-4'-demethyl-4-(3-N,N-dimethylamino-1-propyl)-4-epipodophyllotoxin(Compound 28).

EXAMPLE 29

Synthesis of4-desoxy-4'-demethyl-4-(2-N,N-di-ethylamino-1-ethyl)-4-epipodophyllotoxin(Compound 31)

To a solution of 160 mg (0.25 mmol) of4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-(2-N,N-diethylamino-1-ethyl)-4-epipodophyllotoxin,obtained in Example 15, in 20 ml of ethyl acetate-methanol (1:1) wasadded 20 mg of 10% palladium-on-carbon and the mixture was reacted atroom temperature in hydrogen streams at atmospheric pressure for 10hours. After the catalyst was filtered off, the solvent was removed byconcentration under reduced pressure and the residue was crystallizedfrom diethyl ether to give 102 mg (yield 84.3%) of4-desoxy-4'-demethyl-4-(2-N,N-diethylamino-1-ethyl)-4-epipodophyllotoxin(Compound 31).

EXAMPLES 30 THROUGH 53

Compounds 29, 30, 32 though 53, shown in Table 2, were synthesized inthe same manner as Examples 28 and 29.

                  TABLE 2                                                         ______________________________________                                         ##STR35##                                                                    ______________________________________                                    

Compound: 28

R=-CH₂ CH₂ CH₂ N(CH₃)2.HCl, Yield: 61.5%, Melting point: 240°-243° C., ¹H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 9.74 (1H, brs, N⁺ H), 8.22 (1H, s,4'-OH), 6.89 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.20 (2H, s, 2'-H, 6'-H),5.98 (1H, d, J=1 Hz, --OCH₂ O--), 5.96 (1H, d, J=1 Hz, --OCH₂ O--), 4.43(1H, d, J=5.5 Hz, 1-H), 4.38 (1H, t, J=8 Hz, 11α-H), 4.12 (1H, dd, J=11Hz, 8 Hz, 11β-H), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.12 (1H, dd, J=14.5Hz, 5.5 Hz, 2-H), 3.08 (2H, m, --CH N<), 3.05 (1H, m, 4-H), 2.86 (1H, m,3-H), 2.75 (6H, s, --N(CH₃)₂), 1.84 (1H, m, --CH₂ CH₂ CH₂ N<), 1.76 (1H,m, --CH₂ CH₂ CH₂ N<), 1.61 (1H, m, --CH₂ CH₂ CH₂ N<), 1.41 (1H, m, --CH₂CH₂ CH₂ N<)

Compound: 29

R=-CH₂ CH₂ N(CH₃)₂.HCl, Yield: 81.8%, Melting point: 226°-228° C., ¹H-NMR [Solvent: CD₃ OD]: δ(ppm), 6.81 (1H, s, 5-H), 6.47 (1H, s, 8-H),6.29 (2H, s, 2'-H, 6'-H), 5.93 (1H, d, J=1.0 Hz, --OCH₂ O--), 5.92 (1H,d, J=1.0 Hz, --OCH₂ O--), 4.56 (1H, d, J=5.5 Hz, 1-H), 4.42 (1H, dd,J=8.5 Hz, 7.5 Hz, 11α-H), 4.17 (1H, dd, J=11 Hz, 8.5 Hz, 11β-H), 3.71(6H, s, 3'-OCH₃, 5'-OCH₃), 3.3 (2H, m, --CH₂ N<), 3.24 (1H, m, 4-H),3.17 (1H, dd, J=14.5 Hz, 5.5 Hz, 2-H), 3.05 (1 H, m, 3-H), 2.87 (6H, s,--N(CH₃)₂), 2.19 (1H, m, --CH₂ CH₂ N<), 1.91 (1H, m, --CH₂ CH₂ N<)

Compound: 30 ##STR36##

Yield: 81.0%, Melting point: 240°-242° C. (decomp.), ¹ H-NMR [Solvent:DMSO-d₆ ]: δ(ppm), 9.94 (1H, brs, N^(+H)), 8.23 (1H, s, 4'-OH), 7.05,7.02 (1H, s, 5-H), 6.46 (1H, s, 8-H), 6.20 (2H, s, 2'-H, 6'-H), 5.99(1H, d, J=1.0 Hz, --OCH₂ O--), 5.97 (1H, d, J=1.0 Hz, --OCH₂ O--), 4.45(1H, d, J=5.5 Hz, 1-H), 4.38 (1H, m, 11α- H), 4.15 (1H, m, 11β-H), 3.62(6H, s, 3'-OCH₃, 5'-OCH₃), 3.20 (1H, m, --CH₂ N>), 3.20 ##STR37## 3.12(2H, m, 2-H, 4-H), 2.87 (1H, m, 3-H), 2.8 (1H, m, --CH₂ N<), 2.65 (3H,s, >NCH₃), 2.27 (1H, m, --CH₂ CH₂ N<), ##STR38##

Compound: 31

R=-CH₂ CH₂ N(C₂ H₅)₂, Yield: 84.3%, Melting point: 204°-205° C., ¹ H-NMR[Solvent: CDCl₃ ]: δ(ppm), 6.38 (1H, s, 8-H), 6.24 (2H, S, 2'-H, 6'-H),5.87 (1H, d, J=1.5 Hz, --OCH₂ O--), 5.86 (1H, d, J=1.5 Hz, --OCH₂ O--),5.30 (1H, b, 4'-OH) 4.47 (1H, d, J=5.0 Hz, 1-H), 4.27 (1H, dd, J=9.7 Hz,11α-H), 4.05 (1H, t, J=9 Hz, 11β-H), 3.70 (6H, s, 3'-OCH₃, 5'-OCH₃),3.07 (1H, dt, J=7 Hz, 5 Hz, 4-H), 2.92 (1H, dd, J= 14 Hz, 5 Hz, 2-H),2.88 (1H, dddd, J=14 Hz, 9 Hz, 7 Hz, 5 Hz, 3-H), 2.50 (4H, q, J=7 Hz,--N(CH₂ CH₃)₂), 2.41 (2H, m, --CH₂ CH₂ N<), 1.82 (1H, m, --CH₂ CH₂ N<),1.64 (1H, m, --CH₂ CH₂ N<), 0.99 (6H, t, J=7 Hz, --N(CH₂ CH₃)₂)

Compound: 32 ##STR39## Yield: 72.0%, Melting point: 234°-237° C.(decomp.), ¹ H-NMR [Solvent: CD₃ OD]: δ(ppm), 6.83 (1H, s, 5-H), 6.47(1H, s, 8-H), 6.29 (2H, s, 2'-H, 6'-H), 5.93 (1H, d, J=1 Hz, --OCH₂O--), 5.92 (1H, d, J=1 Hz, --OCH₂ O--), 4.56 (1H, d, J=5.5 Hz, 1-H),4.42 (1H, dd, J=8.5 Hz, 7.5 Hz, 11α-H), 4.14 (1H, dd, J=11 Hz, 8.5 Hz,11β-H), 3.86 (2H, t, J=5.5 Hz, >NCH₂ CH₂ OH), 3.71 (6H, s, 3'-OC₃,5'-OCH₃), 3.3 (2H, m, --CH₂ CH₂ NCH.sub. 2 CH₂ OH), 3.2-3.3 (3H, m, 4-H,--CH₂ CH₂ OH), 3.17 (1H, dd, J=14.5 Hz, 5.5 Hz, 2-H), 3.05 (1H, m, 3-H),2.91 (3H, s, >NCH₃), 2.23 (1H, m, --CH₂ CH₂ NCH₂ CH₂ OH), 1.96 (1H, m,--CH₂ CH₂ NCH₂ CH₂ OH) Compound: 33 ##STR40## Yield: 89.2%, Meltingpoint: 224°-226° C., ¹ H-NMR [Solvent: CD₃ OD]: δ(ppm), 6.81 (1H, s,5-H), 6.45 (1H, s, 8-H), 6.30 (2H, s, 2'-H, 6'-H), 5.93 (1H, d, J=1 Hz,--OCH₂ O--), 5.92 (1H, d, J=1 Hz, --OCH₂ O--), 4.55 (1H, d, J=5.5 Hz,1-H), 4.43 (1H, dd, J=8.5 Hz, 7.5 Hz, 11α-H), 4.16 (1H, dd, J=11 Hz, 8.5Hz, 11β-H), 3.71 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.3 (2H, m, --CH₂ N<) , 3.24(1H, m, 4-H), 3.15 (1H, dd, J=14.5 Hz, 5.5 Hz, 2-H), 3.02 (1H, m, 3-H),2.80 (6H, brs, -N(CH₃)₂), 2.72 (3H, brs, --N(CH₃)-N<), 2.13 (1H, m,--CH₂ CH₂ N<), 1.80 (1H, m, --CH₂ CH₂ N<) Compound: 34 ##STR41## Yield:66.7%, Melting point: 232°-236° C. (decomp.), ¹ H-NMR [Solvent: DMSO-d₆]: δ(ppm), 6.91 (1H, s, 5-H), 6.43 (1H, s, 8-H), 6.23 (2H, s, 2'-H,6'-H), 5.94 (1H, d, J=1 Hz, --OCH₂ O--), 5.93 (1H, d, J=1 Hz, --OCH₂O--), 4.43 (1H, d, J=5.5 Hz, 1-H), 4.35 (1H, dd, J=8 Hz, 11α-H), 4.15(1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.64 (6H, s, 3'-OCH₃, 5'-OCH₃),3.20-3.50 ##STR42## 3.16 (1H, m, 4-H), 3.08 (1H, dd, J=14.5 Hz, 5.5 Hz,2-H), 2.88 (1H, m, 3-H), 2.72 (3H, s, >NCH₃) , 2.17 ##STR43## Compound:35 ##STR44## Yield: 71.7%, Melting point: 203°-205° C., ¹ H-NMR[Solvent: DMSO-d₆ ]: δ(ppm), 6.95 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.23(2H, s, 2'-H, 6'-H), 5.95 (1H, d, J=1 Hz, --OCH₂ O--), 5.94 (1H, d, J=1Hz, --OCH₂ O--), 4.44 (1H, d, J=5.5 Hz, 1-H), 4.36 (1H, dd, J=8 Hz,11α-H), 4.16 (1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.64 (6H, s, 3'-OCH₃,5'-OCH₃), 3.42 (6H, brs, --CH₂ NCH₂ CH₂ N<), 3.17 (1H, m, 4-H), 3.11(1H, dd, J=14 Hz, 5.5 Hz 2-H), 2.90 (1H, m, 3-H), 2.80 (6H, s,--N(CH₃)₂), 2.74 (3H, s, >N(CH₃)₂), 2.26 (1H, m, --CH₂ CH.sub. 2N(CH₃)CH₂ CH₂ N<), 1.89 (1H, m, --CH₂ CH₂ N(CH₃)CH₂ CH₂ N<) Compound: 36##STR45## Yield: 70.0%, Melting point: 251°-253° C., ¹ H-NMR [Solvent:DMSO-d₆ ]: δ(ppm), 10.48 (1H, brs, N⁺ H, ), 8.22 (1H, brs, 4'-OH), 6.96(1H, s, 5-H), 6.46 (1H, s, 8-H), 6.20 (2H, s, 2'-H, 6'-H), 5.99 (1H, s,--CH₂ O--), 5.97 (1H, s, --OCH₂ O--), 4.45 (1H, d, J=5.5 Hz, 1-H), 4.37(1H, t, J=8 Hz, 11α-H), 4.14 (1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.97##STR46## 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.45 ##STR47## 3.40 ##STR48##3.15 (1H, m, 4-H), 3.11 (1H, dd, J=14 Hz, 5.5 Hz, 2-H), 3.06 ##STR49##2.88 (1H, m, 3-H), 2.28 ##STR50## Compound: 37 ##STR51## Yield: 67.4%,Melting point: 170°-172° C., ¹ H-NMR [Solvent: DMSO-d6]: δ(ppm), 7.17##STR52## 6.66 (1H, s, 5-H), 6.39 (1H, s, 8-H), 6.18 (2H, s, 2'-H,6'-H), 5.92 (1H, s, --OCH₂ O--), 5.90 (1H, s, --OCH₂ O--), 4.38 (1H, d,J=5.5 Hz, 1-H), 4.30 (1H, t, J=8 Hz, 11α-H), 4.02 (1H, dd, J=12 Hz, 8Hz, 11β-H), 3.61 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.17 (1H, m, 4-H), 3.09 (1H,dd, J=14.5 Hz, 5.5 Hz, 2-H), 2.84 (1H, m, 3-H), 2.75 (3H, s,--N(CH₃)Ph), 2.69 (2H, m, --CH₂ N(CH₃)--), 2.38 (3H, s, --CH₂ N(CH₃)--), 1.93 (1H, m, --CH₂ CH₂ N<), 1.53 (1H, m, --CH₂ CH₂ N<)Compound: 38 ##STR53## Yield: 66.1%, Melting point: 210°-217° C., ¹H-NMR [Solvent: DMSO-d₆ ]: δ(ppm) 9.73, 9.69 (1H, brs, N⁺ H), 8.23 (1H,4'-OH), 7.00, 6.96 (1H, s, 5-H), 6.46 (1H, s, 8-H), 6.19 (2H, s, 2'-H,6'-H), 5.99 (1H, s, --OCH₂ O--), 5.97 (1H, s, --OCH₂ O--), 4.45 (1H, d,J=5.5 Hz, 1-H), 4.36 (1H, t, J=8 Hz, 11α-H), 4.14, 4.11 (1H, dd, J=10Hz, 8 Hz, 11β-H), 3.62 (6H, s, 3'-OCH₃, 5'-CH3), 3.20 (1H, m, 4-H), 3.14(1H, dd, J=14.5 Hz, 5.5 Hz, 2-H) , 3.09 (1H, brs, --CH₂ CH₂ N(CH₃)CH₂(CH₂)₄ --), 2.96 (1H, brs, --CH₂ CH₂ N(CH₃)CH₂ (CH₂)₄ --) 2.88 (1H, brs,3-H), 2.73 (3H, s, >NCH₃) , 2.23 (1H, m, --CH₂ CH₂ N(CH₃)--), 1.82 (1H,m, --CH₂ CH₂ N(CH₃)--), 1.63 (2H, brs, --CH₂ CH₂ N(CH₃)CH₂ CH₂ (CH₂)₃--), 1.29 (6H, brs, --N(CH₃)CH₂ CH₂ (CH₂)₃ CH₃), 0.88 (3H, t, J=7 Hz,>N(CH₂)₅ CH₃) Compound: 39 ##STR54## Yield: 59.3%, Melting point:239°-244° C. (decomp.), ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 9.63, (1H,brs, N⁺ H), 8.22 (1H, 4'-OH), 7.02 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.20(2H, s, 2'-H, 6'-H), 5.99 (1H, s, --OCH₂ O--), 5.96 (1H, s, --OCH₂ O--),5.44 (1H, s, --OCH₂ O--), 5.96 (1H, s, --OCH₂ O--), 5.44 (1H, t, J=5 Hz,--CH₂ O--), 4.44 (1H, d, J=5 Hz, 1-H), 4.35 (1H, t, J=8 Hz, 11α-H), 4.13(1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.77 (1-H, m, --CH₂ OH), 3.65 (1H, m,--CH₂ OH), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.54 ##STR55## Compound: 40##STR56## Yield: 69.8%, Melting point: 204°-205° C., ¹ H-NMR [Solvent:DMSO-d₆ ]: δ(ppm), 10.76 (1H, brs, N⁺ H), 7.96 (1H, brs, 4'-OH), 7.55##STR57## 7.46 ##STR58## 6.90, 6.86 (1H, s, 5-H), 6.45 (1H, s, 8-H),6.22 (2H, s, 2'-H, 6'-H), 5.98 (1H, d, J=1 Hz, --OCH₂ --), 5.96 (1H, d,J=1 Hz, --OCH₂ O--), 4.45 (1H, d, J=5.5 Hz, 1-H), 4.39 ##STR59## 4.31(1H, m, 11α-H), 4.22 ##STR60## 4.11 (1H, brt, J=8.5 Hz, 11β-H), 3.64(6H, s, 3'-OCH₃, 5'-OCH₃), 3.10 (1H, over lapped, 2-H), 2.89 (1H, m,3-H), 2.67 (3H, brs, >NCH₃), 2.33 (1H, m, --CH₂ CH₂ N<), 1.96 (1H, m,--CH₂ CH₂ N<) Compound: 41 ##STR61## Yield: 67.0%, Melting point:222°-225° C., ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm) 9.29 (1H, brs, N⁺ H),7.96 (1H, brs, 4'-OH), 6.95 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.23 (2H,s, 2'-H, 6'-H), 5.97 (1H, d, J=1 Hz, --OCH₂ O--), 5.96 (1H, d, J=1 Hz,--OCH₂ O--), 5.24 (2H, brs, --CH(CH₂ OH)₂), 4.45 (1H, d, J=5.5 Hz, 1-H), 4.36 (1H, t, J=8 Hz, 11α-H), 4.17 (1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.73(4H, brs, --CH(CH₂ OH)₂), 3.64 (6 H, s, 3'-OCH₃, 5'-OCH₃), 3.2-3.5 (2H,m, --CH₂ CH₂ N<), 3.39 (1H, brs, --CH(CH₂ OH)₂), 3.15 (1H, m, 4-H), 3.09(1H, over lapped, 2-H), 2.89 (1H, m, 3-H), 2.81 (3H, brs, >NCH₃), 2.28(1H, m, --CH₂ CH₂ N<), 1.91 (1H, m, --CH₂ CH₂ N<) Compound: 42 ##STR62##Yield: 66.0%, Melting point: 210°-216° C., ¹ H-NMR [Solvent: DMSO-d₆ ]:δ(ppm) 11.30 (1H, brs, N⁺ H), 10.78 (1H, brs, N⁺ H), 8.23 (1H, brs,4'-OH), 7.00 (1H, brs, 5-H), 6.46 (1H, s, 8-H), 6.20 (2H, s, 2'-H,6'-H), 5.99 (1H, s, --OCH₂ O--), 5.97 (1H, s, --OCH₂ O--), 4.45 (1H, d,J=5.5 Hz, 1-H), 4.37 (1H, t, J=8 Hz, 11α-H), 4.15 (1H, m, 11β-H), 3.62(6H, s, 3'-OCH₃, 5'-OCH₃), 3.16 (1H, m, 4-H), 3.14 (1H, dd, J=14.5 Hz,5.5 Hz, 2-H), 3.0-4.1 ##STR63## 2.89 (1H, m, 3-H), 2.83 (3H, brs,>NCH₃), 2.30 (1H, m, --CH₂ CH₂ N<), 1.91 (1H, m, --CH₂ CH₂ N<) Compound:43 ##STR64## Yield: 69.0%, Melting point: 210°-213° C., ¹ H-NMR[Solvent: DMSO-d₆ ]: δ(ppm) 10.41 (1H, brs, N⁺ H), 10.72, 10.66 (1H,brs, N⁺ H), 8.24 (1H, brs, 4'-OH), 7.03, 6.97 (1H, brs, 5-H), 6.47 (1H,s, 8-H), 6.20 (2H, s, 2'-H, 6'-H), 5.99 (1H, s, --OCH₂ O--), 5.97 (1H,s, --OCH₂ O--), 4.45 (1H, d, J=5.5 Hz, 1-H), 4.37 (1H, t, J=7.5 Hz,11α-H), 4.17, 4.13 (1H, m, 11β-H), 3.63 ##STR65## Compound: 44 ##STR66##Yield: 61.0%, Melting point: 250°-252° C., ¹ H-NMR [Solvent: DMSO-d₆ ]:δ(ppm) 9.48 (1H, brs, N⁺ H), 8.23 (1H, s, 4'-OH), 6.96 (1H, 5-H), 6.46(1H, s, 8-H), 6.19 (2'-H, s, 6'-H), 4.45 (1-H, d, J=5.5 Hz, 1-H), 4.37(1H, t, J=8 Hz, 11α-H), 4.12 (1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.62 (6H,s, 3'-OCH₃, 5'-OCH₃), 3.44 ##STR67## Compound: 45 ##STR68## Yield:65.4%, Melting point: 280° C. (decomp.), ¹ H-NMR [Solvent: DMSO-d₆ +D₂O(2:1)]: δ(ppm), 6.87 (1H, s, 5-H), 6.49 (1H, s, 8-H), 6.25 (2H, s,2'-H, 6'-H), 5.95 (2H, s, --OCH₂ O--), 4.51 (1H, d, J=5.5 Hz, 1-H), 4.44(1H, t, J=8 Hz, 11α-H), 4.13 (1H, dd, J=11 Hz, 8 Hz, 11β-H), 3.68 (2H,m, ##STR69## Compound: 46 ##STR70## Yield: 92.0%, Melting point:193°-195° C., ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 8.26 (1H, s, 4'-OH),6.97 (1H, d, J=7.9 Hz, 5-H), 6.46 (1H, s, 8-H), 6.20 (2H, s, 2'-H,6'-H), 5.99 (1H, s, --OCH₂ O--), 5.97 (1H, s, --OCH₂ O--), 4.45 (1H, d,J=5.6 Hz, 1-H), 4.36 (1H, t, J=7.2 Hz, 11α-H), 4.17 (1H, m, 11β-H), 3.69(2H, m, --CH₂ OCH₃), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.30 (3H, s, --CH₂OCH₃), 2.82-3.39 (7H, m, 2-H, 3-H, 4-H, --CH₂ NCH₂ --), 2.76 (3H, s,>NCH₃), 2.29 (1H, m, --CH₂ CH₂ N<) 1.86 (1H, m, --CH₂ CH₂ N<) Compound:47 ##STR71## Yield: 41.5%, Melting point: 195°-197° C., ¹ H-NMR[Solvent: DMSO-d₆): δ(ppm), 11.37 (1H, br, N⁺ H), 11.17 (1H, br, N⁺ H),8.20 (1H, br, 4'-OH), 7.05, 7.00 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.19(2H, s, 2'-H, 6'-H), 5.99 (1H, s, --OCH₂ O--), 5.96 (1H, s, --OCH₂ O--),4.45 (1H, d, J=5.6 Hz, 1-H), 4.37 (1H, t, J=7.2 Hz, 11α-H), 4.10-4.30(1H, m, 11β-H), 3.61 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.00-3.60 (12H, m, 2-H,4-H, --CH₂ NCH₂ CH₂ N(CH₂ CH₃)₂), 2.90 (1H, m, 3-H), 2.81 (2H, s,>NCH₃), 2.32 (1H, m, --CH₂ CH₂ N<), 1.91 (1H, m, --CH₂ CH₂ N<), 1.26(6H, t, --N(CH₂ CH₃)₂) Compound: 48 ##STR72## Yield: 31.0%, Meltingpoint: 181°-183° C., ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 8.85 ##STR73##6.90, 7.00 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.18 (2H, s, 2'-H, 6'-H),5.99, 5.97 (2H, s, --OCH₂ O--), 4.10-4.70 (5H, m, 1-H, --N 3.61 (6H, s,3'-OCH₃, 5'-OCH₃), 3.00-4.00 (4H, m, --CH₂ CH₂ N<, 2-H, 4-H), 2.90 (1H,m, 3-H), 2.67 (3H, s, >NCH₃), 2.40 (1H, m, --CH₂ CH₂ N<), 2.00 (1H, m,--CH₂ CH₂ N<) Compound: 49 ##STR74## Yield: 57.0%, Melting point:185°-186 ° C., ¹ H-NMR [Solvent: DMSO-d₆)]: δ(ppm ), 8.68 ##STR75## 6.95(1H, s, 5-H), 6.44 (1H, s, 8-H), 6.19 (2H, s, 2'-H, 6'-H), 5.99, 5.97(2H, s×2, --OCH₂ O--), 4.50 ##STR76## 4.44 (1H, d, J=5.3 Hz, 1-H), 4.32(1H, t, J=7.9 Hz, 11α-H), 4.17 (1H, m, 11β-H), 3.62 (6H, s, 3'-OCH₃,5'-OCH₃), 3.11-3.40 (4H, m, 2-H, 4-H, --CH₂ CH₂ N<), 2.89 (1H, m, 3-H),2.76 (3H, s, >NCH₃), 2.40 (1H, m, --CH₂ CH₂ N<), 1.99 (1H, m, --CH₂ CH₂N<) Compound: 50 ##STR77## Yield: 92.0%, Melting point: 238° C.(decomp.), ¹ H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 8.26 (1H, s, 4'-OH),7.03 (1H, s, 5-H), 6.45 (1H, s, 8-H), 6.19 (2H, s, 2'-H, 6'-H), 5.99,5.97 (2H, s×2, --OCH₂ O--), 4.44 (1H, d, J=5.2 Hz, 1-H), 4.37 (1H, m,11α-H), 4.34 (1H, m, 11β-H), 3.62 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.90-3.40(9H, m, 2-H, 3-H, 4-H, --CH₂ NCH₂ CH₂ CH2N<), 2.75 (9H, m,--N(CH₃)-(CH₂)₃ N(CH₃)₂), 1.91-2.34 (4H, m, --CH₂ CH₂ NCH₂ CH₂ CH₂ N<)Compound: 51 ##STR78## Yield: 75.0%, Melting point: 198°-199° C., ¹H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 11.0 (2H, br, N⁺ H), 8.26 (1H, s,4'-OH), 7.05 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.19 (2H, s, 2'-H, 6'-H),5.99 (2H, s, --OCH₂ O--), 4.18-4.43 (3H, m, 1-H, 11α-H, 11β-H), 3.62(6H, s, 3'-OCH₃, 5'-OCH₃), 2.51-3.62 (9H, m, 2-H, 3-H, 4-H, --CH₂ NCH₂(CH₂) CH₂ N<), 2.75 (6H, s, --N(CH₃)₂), 2.27 (1H, m, --CH₂ CH₂ N(CH₂)₆N<), 1.85 (1H, m, --CH₂ CH₂ N(CH₂)₆ N<), 1.65, 1.33 (8H, m, --NCH₂(CH₂)₄ CH₂ N<) Compound: 52

R=-CH₂ CH₂ NHCH₂ CH₂ N(CH₃)₂.2HCl, Yield: 55.0%, Melting point: 213° C.(decomp.), ¹ H-NMR [Solvent: CDCl₃ +CD₃ OD]: δ(ppm), 6.80 (1H, s, 5-H),6.47 (1H, s, 8-H), 6.27 (2H, s, 2'-H, 6'-H), 5.95 (1H, d, J=1 Hz, --OCH₂O--), 5.94 (1H, d, J=1 Hz, --OCH₂ O--), 4.55 (1H, d, J=4.5 Hz, 1-H),4.41 (1H, m, 11α-H), 4.26 (1H, 3.76 (6H, s, 3'-OCH₃, 5'-OCH₃), 3.61 (2H,brt, J=6 Hz, --NHCH₂ CH₂ N<) 3.47 (2H, brt, --NHCH₂ CH₂ N<), 3.27 (1 H,m, 4-H), 3.15 (2H, m, --CH₂ NHCH₂ CH₂ N<), 3.05 (2H, over lapped, 2-H,3-H), 2.96 (6H, s, --N(CH₃)₂), 2.27 (1H, m, --CH₂ CH₂ NHCH₂ CH₂ N<),2.04 (1H, m, --CH₂ CH₂ NHCH₂ CH₂ N<)

Compound: 53 ##STR79## Yield: 67.0%, Melting point: 188°-190° C., ¹H-NMR [Solvent: DMSO-d₆ ]: δ(ppm), 13.00 (2H, br, N⁺ H), 10.94 (1H, br,4'-OH), 7.05 (1H, s, 5-H), 6.44 (1H, s, 8-H), 6.19 (2H, s, 2'-H, 6'-H),5.98 (2H, s, --OCH₂ O--), 4.45 (2H, m, 1-H, 11α-H), 4.12 (1H, m, 11β-H),3.61 (6H, s, 3'-OCH₃, 5'-OCH₃), 2.20-3.60 ##STR80## 2.92 ##STR81## 2.28(1H, m, --CH₂ CH₂ N(CH₃)--), 2.04 (1H, m, --CH₂ CH₂ N(CH₃)--)Pharmacological Test 1

A 96-well plate was inoculated with 1×10³ cells/well of P388 mouseleukemia cell line and incubated for 24 hours. The test compound wasdissolved in dimethylformamide and the solution was diluted with mediumto various concentrations and added to respective wells. The plate wasfurther incubated for 3 days, after which it was fixed withglutaraldehyde and stained with crystal violet for cytometry. Thecytocidal effect of each compound was expressed as the concentrationcausing a 50% decrease in cell count (ED₅₀) as compared with thecontrol. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Compound No.    ED.sub.50 (M)                                                 ______________________________________                                        3               4.5 × 10.sup.-7                                         5               1.2 × 10.sup.-7                                         28              1.2 × 10.sup.-8                                         33              2.0 × 10.sup.-8                                         34              3.0 × 10.sup.-9                                         35              1.0 × 10.sup.-9                                         38              1.9 × 10.sup.-8                                         43              4.1 × 10.sup.-9                                         44              1.2 × 10.sup.-8                                         45              3.3 × 10.sup.-9                                         47              6.3 × 10.sup.-9                                         52              4.0 × 10.sup.-8                                         53              4.3 × 10.sup.-9                                         ______________________________________                                    

Pharmacological Test 2

L1210 mouse leukemia cell line, 1×10⁵ cells/mouse, was intraperitoneallytransplanted into 7-weeks-old male CDF₁ mice (6 per group). The testcompound, in the varying amounts shown below in Table 4, was dissolvedin physiological saline containing 3.5% of dimethyl sulfoxide and 6.5%of Tween 80 and the solution was intraperitoneally administered for 5days following the transplantation of cells for a total of 5 times. Thepercent life-prolonging effect of the compound was determined bycomparison with a group given physiological saline containing 3.5% ofdimethyl sulfoxide and 6.5% of Tween 80 only. The results are shown inTable 4.

                  TABLE 4                                                         ______________________________________                                        Compound     Dosage     Life-prolonging                                       No.          (mg/kg/day)                                                                              effect (%)                                            ______________________________________                                        36           10         81                                                    43           5          257                                                   45           2.5        231                                                   ______________________________________                                    

Preparation Examples using the compound of the invention are presentedbelow.

Preparation Example 1 Tablets

According to the following formula, tablets were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 34          100        mg                                            Lactose              47         mg                                            Corn starch          50         mg                                            Crystalline cellulose                                                                              50         mg                                            Hydroxypropylcellulose                                                                             15         mg                                            Talc                 2          mg                                            Magnesium stearate   2          mg                                            Ethylcellulose       30         mg                                            Unsaturated fatty acid glyceride                                                                   2          mg                                            Titanium dioxide     2          mg                                            Per Tablet           300        mg                                            ______________________________________                                    

Preparation Example 2 Granules

According to the following formula, granules were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 35        200        mg                                              Mannitol           540        mg                                              Corn starch        100        mg                                              Crystalline cellulose                                                                            100        mg                                              Hydroxypropylcellulose                                                                           50         mg                                              Talc               10         mg                                              Per Wrapper        1,000      mg                                              ______________________________________                                    

Preparation Example 3 Fine Granules

According to the following formula, fine granules were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 43        200        mg                                              Mannitol           520        mg                                              Corn starch        100        mg                                              Crystalline cellulose                                                                            100        mg                                              Hydroxypropylcellulose                                                                           70         mg                                              Talc               10         mg                                              Per Wrapper        1,000      mg                                              ______________________________________                                    

Preparation Example 4 Capsules

According to the following formula, capsules were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 45      100          mg                                              Lactose          50           mg                                              Corn starch      47           mg                                              Crystalline cellulose                                                                          50           mg                                              Talc             2            mg                                              Magnesium stearate                                                                             1            mg                                              Per capsule      250          mg                                              ______________________________________                                    

Preparation Example 5 Injections

According to the following formula, injections were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 47         100        mg                                             Distilled water for injections                                                                    q.s.                                                      Per ampule          2          ml                                             ______________________________________                                    

Preparation Example 6 Suppositories

According to the following formula, suppositories were prepared by theestablished pharmaceutical procedure.

    ______________________________________                                        Compound 53                 100    mg                                         Witepsol S-55               1,400  mg                                         (a mixture of mono-, di- and triglycerides of saturated                       fatty acids from lauric acid to stearic acid, product of                      Dynamite Nobel)                                                               Per suppository             1,500  mg                                         ______________________________________                                    

We claim:
 1. A 4-desoxy-4-epipodophyllotoxin derivative of the generalformula: ##STR82## wherein R₁ is a hydrogen atom, R is a group of theformula --(CH₂)_(n) NR₂ R₃ (where n is an integer of 1 to 4); R₂ and R₃are the same or different and each is a hydrogen atom, a group of theformula --N(Ra)(Rb) (where Ra and Rb are the same or different and eachis a lower alkyl group) or a lower alkyl group which may be substitutedby hydroxy or a group of the formula --N(Rc)(Rd) (where Rc and Rd arethe same or different and each is a lower alkyl group); or apharmaceutically acceptable salt thereof.
 2. The4-desoxy-4-epipodophyllotoxin derivative or a pharmaceuticallyacceptable salt thereof according to claim 1 wherein n is 2 or
 3. 3. The4-desoxy-4-epipodophyllotoxin derivative or a pharamaceuticallyacceptable salt thereof according to claim 1 which derivative is4-desoxy-4'-demethyl-4-[2-[N-[2-(N',N'-dimethylamino)ethyl]-N-methylamino]ethyl]-4-epipodophyllotoxin.